Dihydroquinidine galacturonates



United States Patent 3,479,359 DIHYDROQUINIDINE GALACTURONATES AlfredHalpern, Great Neck, N.Y., assignor to Synergistics, Inc., New York,N.Y., a corporation of New York No Drawing. Continuation-impart ofapplication Ser. No. 535,736, Mar. 21, 1966. This application Sept. 23,1968,

Ser. No. 761,819

Int. Cl. C07d 43/24; A61k 27/00 U.S. Cl. 260-284 3 Claims ABSTRACT OFTHE DISCLOSURE Dihydroquinidine polygalacturonate and dihydroquinidinegalacturonate are described together with the method for theirpreparation and method for achieving a therapeutic effect.

This application is a continuation-in-part of applicants copendingapplication, Ser. No. 535,736, filed Mar. 21, 1966 now abandoned, whichwas a continuation-in-part of applicants then copending application,Ser. No. 373,827, filed June 9, 1964, now abandoned, which was acontinuation-in-part of applicants then copending application, Ser. No.144,263, filed Oct. 10, 1961, now abandoned.

This invention relates to new therapeutically important derivatives ofthe alkaloid dihydroquinidine which are formed by the interaction of aglycose component and the alkaloidal radical. In particular, thisinvention is concerned with dihydroquinidine polygalacturonate anddihydroquinidine galacturonate, the methods for their preparation,pharmaceutical compositions containing these compounds and the method ofreversing a cardiac arrhythmia by administration of the newdihydroquinidine glycose compounds and compositions containing saidcompounds.

Disorders in the rhythm of the heart are among the very common problemsencountered in medical practice. It has been estimated that about 25percent of the average cardiac population presents the problems ofdisordered heart rhythm. The cardiac arrhythmias are most often treatedwith drugs alfecting the conduction of the pacemaker impulse controllingthe rhythmicity of the heart.

While cinchona bark contains more than twenty alkaloids, quinidine isthe most important member of this group indicated for the treatment ofdisorders of the heart and the largest part of the clinical literatureon the cardiac action of the cinchona alkaloids relates entirely toquinidine. Disorders of the cardiac rhythm constitute the onlytherapeutic indication for the use of quinidine in disturbances of theheart. It has no primary place in the treatment of cardiac pain orfailure. While under some conditions quinidine acts to prevent orabolish cardiac pain or failure, such results are due neither to thedirect dilation of the coronary arteries nor to the direct action of theforce of contraction of the cardiac muscles, and quinidine remains thedrug of choice in the treatment of abnormal rhythms of the heart.

Some of the inherent limitations to the use of quinidine in clinicalcardiology and the experimental approaches to correct these aredescribed in the U.S. Patent 2,878,252. Clinical literature recognizesstill another problem associated with the use of quinidine to correctthe abnormal heart rhythm and that is, effective only in approximately75 percent of the cardiac arrhythmias. While a portion of these patientswho are not benefited by the administration of the older quinidinecompound may be benefited by the administration of the newer quinidinecompound derivatives, there remains a significant group for whomquinidine exerts no therapeutic affect on their cardiac arrhythmias.This group of patients are often treated with 3,479,359 Patented Nov.18, 1969 other potent agents such as digitalis, adrenergic drugs andprocaine amide, but usually without significant affect and thearrhythmia continues to persist for the remainder of their lives,causing varying degrees of limitation and distress.

Among the alkaloids isolated from the cinchona plant is the hydrogenatedform of quinidine. This compound is known as dihydroquinidine and may bedistinguished from quinidine in its chemical, physical, pharmacologicand therapeutic properties. Irrespective of the structural relationshipbetween quinidine and dihydroquinidine, there is a marked contrast inbehavior of the hydrogenated and the compounds. Apart from the wellknown generic differences between the hydrogenated and unhydrogenatedcompounds, these separate entities have their own level of chemicalreactivity and toxicologic reactivity, and the chemical behavior of onemember of the cinchona alkaloid group may not be imputed to anothermember of the same group. Thus, it is known that the presence of anunsaturated or unhydrogenated linkage in an organic compound willinterfere with physiologic enzyme reactions and also that the hydrogenunsaturation of an organic compound may convert an essentially benignsubstance into a noxious irritant as for example, compare the propertiesof allyl alcohol and its saturated analog, propyl alcohol. The U.S.Patent No. 2,230,631, notes on Col. 1 (lines 36 through 52), thatdihydroquinidine nicotinate is a crystalline solid melting at 209 C. andis slightly soluble in water. The very next paragraph, Col. 1 (lines5268) of the same reference, describes the preparation and properties ofquinidine nicotinate as a non-crystalline substance, without a meltingpoint and which is easily soluble in water. Here we find that a physicaland chemical change in the state of matter and its properties resultsfrom the simple chemical reaction of a salt formation when nicotinicacid is reacted with the separate reagents, quinidine andhydroquinidine. Whereas the hydrogenated dihydroquinidine produces acrystalline, slightly watersoluble reaction-product; the dehydrogenatedquinidine results in a non-crystalline glassy material, which is easilysoluble in water.

Pharmacologically quinidine may be distinguished from dihydroquinidinein that the dose of dihydroquinidine required to abolish theafter-affects to faradic stimulation was higher than that of quinidine.The toxicity of dihydroquinidine in mice is about 18 percent greaterthan the pure quinidine. Dihydroquinidine, (Chem. Abstracts, 48: 9543b,1954), is reported to reduce muscle potassium and accelerate liver andmyocardial potassium loss during therapeutic use. This effect is incontradistinction to the properties of quinidine, which has beenreported to augment muscle potassium (Proc. Soc. Exper. Med. & Biol.,92: 629, 1956) (Am. J. Physiol. 199: 151, 1960). While the earlyreferences to a therapeutic equivalence of dihydroquinidine andquinidine appeared approximately 40 years ago, in the interim, moredefinitive experimental techniques have been developed and as a resultof the broadening of the knowledge in this specialized fieldtherapeutics, many limitations to the older experimental procedures havebeen established. Thus, some investigators, as for example Van Dongen,(Arch. Internat. de Pharmacodyn et de Therap., 63: -94, 1939) whooriginally suggested that dihydroquinidine may be a more cardiotoxicsubstance than quinidine, he later abandoned this concept after hiscontinued research, (Arch. Internat. Pharmacodyn, et de Therap., 91:399-403, 1952). De Boer also assumed, in 1936 (Proc. Acad. Sci.,Amsterdam, 39: 266- 271, 1936) that dihydroquinidine was a betteranti-fibrillatory agent than is quinidine but on the basis of hissubsequent studies (Arch. Internat. de Pharmacodyn et de Therap., 51:246-254, 1939) he reversed his position and concluded that quinidine isthe more suitable therapeutic agent. A study of the literatureestablishes that many of the earlier works later reversed their opinionsregarding the relative activity of quinidine and dihydroquinidine and inview of the many inconsistent findings in the scientific literature, itis now well accepted that the therapeutic properties determined for onecinchona derivative may not be imputed to another cinchona compound.

It was found that dihydroquinidine polygalacturonate anddyhydroquinidine galacturonate are especially useful to correctarrhythmias in those patients who are refractory to the conventionalforms of quinidine and who would otherwise remain cardiac invalids, withserious threat to their life.

A comparative clinical study of quinidine polygalacturonate, quinidinehydrochloride and dihydroquinidine polygalacturonate was conducted in aseries of 21 patients presenting cardiac arrhythmias. Each of thepatients received a complete physical examination which includedelectrocardiographic analysis of the patients cardiac status prior tothe start of the study. The method of study utilized was as follows: Thepatients were prescribed one of the test compounds, to wit: quinidinepolygalacturonate, dihydroquinidine polygalacturonate and quinidinehydrochloride and the cardiodynamic effects observed. A

cross-over procedure was then utilized with the patients receivinganother test compound for clinical comparison of the cardiodynamiceffects. In this manner, the specific antiarrhythmic properties of therespective test compounds were compared within the same patient. Thus, 7patients were first treated with quinidine hydrochloride and then withdihydroquinidine polygalacturonate and 11 patients were treated firstwith quinidine polygalacturonate and then with dihydroquinidinepolygalacturonate. The results of this study are presented in Table I,following, The conclusions of the investigator, based upon the resultsof his study of the effects of quinidine hydrochloride, quinidinepolygalacturonate and dihydroquinidine polygalacturonate in the seriesof patients described in Table I, are as follows:

(a) The total therapeutically successful dosage administration fordihydroquinidine polygalacturonate is lower than that amount requiredfor quinidine hydrochloride and quinidine polygalacturonate. The controlof the arrhythmia could generally be achieved on lower daily dosage ofdihydroquinidine polygalacturonate than with either quinidinehydrochloride or quinidine polygalacturonate. Dihydroquinidinepolygalacturonate exerts more protracted and pronounced cardiodynamiceffects than quinidine polygalacturonate.

TABLE I.RESULTS OF CLINICAL STUDY Duration of Drug Therapy Patient AgeDiagnosis Administered Dosage (days) Results Side Efiects 1.... LE. 34Massive ventricular extra- Q.Hcl 1 1 tablet t.i.d 3 Decrease ofventricular Considerable systoles; intermittent extra-systoles; from 15diarrhea and paroxysmal tachycardia; per minute to 5-8 per nausea.labile hypertension. 2 tablet t.i.d 6 minute.

D.I'I.Q,.P.G.2 1 tablet b.i. 8 Complete disappearance of None.

extra-systoles. W

2...- LS. 42 Ventricular extra-systolcs. Q.Hcl 1 tablet t.i.d 3 Noeffect. Diarrhea.

D.H.Q.P. G. 1 tablet b.i.d 7 Complete disappearance of None.

extra-systoles.

8..-- E.D. 63 Coronary heart disease; Q.Hcl 1 tablet t.i.d 2 Decrease ofsupra-ventric- Do.

massive supra-ventricular 1 tablet q.i.d 2 ular extra-systoles to 4-8extra-systoles. per minute.

D.H.Q.P.G. 1 tablet b.i.d 4 Complete disappearance of Do.

supra-ventricular extrasystoles.

4 M.S. 57 Coronary heart disease; Q.Hel 1 tablet t.i.d..- 4 No effect onextra-systoles. Do. ventricular extra-systoles. D.H.Q.P G 1 tablett.i.d. 11 Complete disappearance of Do.

extra-systolcs.

5 H.W. 71 Coronary heart disease; Q,.Hcl 1 tablet q.i.d 6 Reduction ofextra-systoles Do.

supra-ventricular and from average of 12 per ventricular extra-systolcs.minute to 4-7 per minute.

D.H.Q,.P.G. 1 table b.1.d 8 Reduction of extra-systoles Do.

to 1-3 per minute.

6 11.1); 65 Coronary heart disease; Q.Hcl 1 tablet q.i.d 3 Reduction ofextra-systoles Nausea.

ventricular extra-systoles. from 10-15 per minute,

to 6-8 per minute. D.H.Q.P.G. 1 tablet b.i.d.. 2 No effect None.

1 tablet t.i.d 3 Reduction of extra-systoles Do to 1-3 per minute(occasional).

7.... 8.13. 51 Coronary heart disease; to Q,.Hcl 1 tablet t.i.d 3 Slightdecline of ventricular Do.

some extent in form of extra-systoles, no effect salvos. on salvo-typerhythm interference.

2 tablets t.i.d 3

D.I-I.Q.P.G. 1 tablet b.i.d.... 3 Reduction of extra-systoles, Do.

salvo-type extra-systoles still sporadic.

1 tablet 4 Reduction in extra-systolcs; Do.

occasional 1-4 per minute; no salvo extra-systoles detectable.

8.-.. St. A. 69 Coronary heart disease; Q.P.G. 1 tablet b.l.d 4Reduction in extra-systoles Do.

supra-ventricular and from 10-14 per minute to ventricularextra-systoles. 3-6 per minute.

D.H.Q.P.G. 1 tablet b.i.d 4 Complete disappearance of 'Do. I extra-s3stoles.

9 KW. 34 Post-operative mltral Q,.P.G. 1 tablet q.1.d 3 Reduction ofbigeminal Do.

stenos 1s ventr1 cular rhythm to 3 per minute. extra-systoles.D.H.Q.P.G. 1 tablet t.i.d 13 Complete disappearance of Do.

extra-systoles.

10 MD. 56 Ventricular extra-systoles Q.P.G. 1 tablet t.i .d 4 Reductionof extra-systoles Do.

post-myocardialinfarction. from 21 to 6 per minute. Ventricular heartdisease. D.H.Q,.P.G. 1 tablet b.i.d 11 Complete disappearance of D0.

extra-systoles.

11.-. IF. 66 Coronary heart disease; Q.P.G. 1 tablet b.i.d 4 Reductionof previous Do.

aur rcular extra-systoles irregularity, and to some intermittentcerebral blood extent salvo-type extraflow disturbance. systoles, to 6:1extrasystoles. D.H.Q,.P.G. 1 tablet b.1.d 4 Complete disappearance ofDo.

extra-systoles.

TABLE I.RESULTS OF CLINICAL STUDY-Continued Duration of Drug TherapyPatient Age Diagnosis Administered Dosage (days) Results Side EifectS12... 8.0. 71 Complete A-V block; Q.P.G. 1 tablet q.i.d.- Reduction ofpara-systoles Occasional Pacemaker implantat ion, from 12 per minute to4-7 nausea and considerable para-systoles; per minute. diarrhea. fullydigitalized. D.H.Q.P.G. 1 tablet b.i.d. 16 Reduction of para-systolesNone.

to 1-4 per minute.

13... S.T. 67 Complete A-V block; Q,.P.G. 1 tablet q.i.d.. 4 Reductionof para-systoles Do.

Pacemaker implantation; from per minute to considerable para-systoles; 4per minute. completely digitalized. D.H.Q.P.G. 1 tablet b.1.d.- 7Reduction to 3-5 para- Do.

. systoles per minute.

14--. W.S. 27 Post-operative mitral Q.P.G. 1 tablet t.i .d 2 No effectDo, stenosis; unstable D.H.Q.P G 1 tablet q.i.d- 2 Normal sinus rhythmDo. ventricular stroke sequence restored. auricular arrhythmia.

15--. S.V. 65 Total A-V block; Pacemaker Q.P.G 1 tablet t.i.d 4Reduction in para-systoles Do.

implantation; para-extrafrom 10 to 13 per minute systoles; fullydigitalized. to 2-4 per minute.

D.H.Q.P.G. 1 tablet b.i.d. 17 Reduction in para-systoles Do.

to 1-5 per minute.

16... KO. 56 Total A-V block; para- Q.P.G. 1 tablet 6X daily 9 Decreasefrom 15 para- Do.

systoles; fully digitalized. systoles per minute to I 4-5 per minute.D.H.Q,.P.G. 1 tablet t.1.d......- 7 Para-systoles decreased Do.

to 3-5 per minute.

17... ND. 24 Post-operative atrial septum Q.P.G. 1 tablet t.i.d.. 4Decrease in polytopio Nausea.

defect; massive supraextra-systoles from 17-20 ventricular andventricular per minute to 2-7 per extra-systoles. I minute.

D.H.Q,.P.G. 1 tablet b.i.d 12 Continued occurrence oi None.

extra-systoles; after 4 days complete disappearance.

18... EN. 27 Unstable ventricular stroke Q.P.G. 1 tablet q.i.d. 6Extra-systoles of 12-18 per Do.

sequence associated with minute reduced to 5 per mitral stenosis,auricular minute. arrhythmia, strong extra- D.H.Q.P.G. 1 tablett.1.d....... 14 Slight extra-systoles, 2-5 Do. systoles, fullydigitalized. per minute.

19... R.R. 74 Coronary heart disease; Q.P. G. 1 tablet t.i.d 2 Completedisappearance of Do.

ventricular extra-systoles. extra-systoles.

20... RS. 47 Cardiac decompensation; D.H.Q.P.G. 1 tablet b.i.d--. 13Complete disappearance of Do.

ventricular extra-systoles. extra-systoles.

21... TH. 70 Relative coronary D.H.Q.P.G. 1 tablet b.i.d. 7 Reduction ofextra-systoles Do.

insuthciency; sclerotic from 7-16 per minute to aortic stenosis;coronary 1-6 per minute.

heart disease; ventricular extra-systoles.

1 Q.Hcl=Quinidine hydrochloride, each tablet containing 200 mg. ofquinidine hydrochloride. 2 D.H.Q.P.G.=Dihydroquinidinepolygalacturonate, each tablet conta1ning 292. 08 mg. ofdihydroquinidine polygalacturonate. 3 Q.P.G.=Quinidinep'olygalacturonate, each tablet containing 300 mg. of quinidinepolygalacturon ate.

(b) Dihydroquinidine polygalacturonate did not cause any side reactionssuch as nausea or diarrhea, which were observed after administration ofquinidine polygalacturonate and quinidine hydrochloride. This absence ofgastrointestinal irritation is important, since dihydroquinidinepolygalacturonate was administered after the onset of side reactionswith quinidine polygalacturonate or quinidine hydrochloride, in the samepatient.

(0) The superior properties of dihydroquinidine polygalacturonate ascompared with quinidine hydrochloride and quinidine polygalacturonate,could not have been anticipated from a knowledge of the literature andthe known behavior of these compounds.

The clinical study of dihydroquinidine polygalacturonate, describedabove, was subjected to statistical analysis to determine thesignificance of the therapeutic results obtained utilizing theChi-square Test for frequency differences and the Students t Test fordosage requirement diiferences.

When frequencies of the therapeutic antiarrhythmic effects ofdihydroquinidine polygalacturonate were compared with the frequencies ofthe therapeutic antiarrhythmic effects of quinidine hydrochloride by acrossover technique, it was determined that dihydroquinidinepolygalacturonate possessed a significantly higher therapeuticantiarrhythmic action than did quinidine hydrochloride. The calculatedvalue of chi-square for this distribution of frequencies (Yatescorrection for continuity applied) exceeded the th percentile of theChi-square Distribution, to Wit, P(X =4.57) 5% for 1 degree of freedom.

When frequencies of therapeutic antiarrhythmic effects ofdihydroquinidine polygalacturonate were compared with the frequencies oftherapeutic antiarrhythmic effects obtained after quinidinepolygalacturonate by a cross-over technique, the results of therapy withdihydroquinidine polygalacturonate was demonstrated to exhibit asignificantly higher proportion of superior antiarrythmic effects. Thecalculated value of chi-square for this observed distribution offrequencies (Yates correction for continuity applied) exceeded the99.5th percentile of the Chi-square Distribution, to wit: P(X =9.625)0.O05 for 1 degree of freedom.

The significance of observed differences in the mean daily dosagerequirements for the respective drugs, to wit: dihydroquinidinepolygalacturonate, quinidine hydrochloride and quinidinepolygalacturonate were compared utilizing the Students t Test. It wasfound that the mean daily dosage requirement of dihydroquinidinepolygalacturonate was significantly lower than the mean daily dosagerequirement of quinidine hydrochloride since the I value, based upon thediiference between these two mean dosage requirements, was between the98th and 99th percentile of the t Distribution, to wit: P(t=8.=632) 2%.The mean daily dosage requirement of dihydroquinidine polygalacturonatewas also found to be significantly lower than the mean daily dosagerequirement for quinidine polygalacturonate since the if value basedupon the difference between these two mean dosage requirements exceededthe 99.95th percentile of the 1 Distribution, to wit: P(t=9.60) 0.1%.

The significance of the differences in frequencies observed in theoccurrence of side-reactions after the administration of the respectivedrugs used in the above study was subjected to statistical analysis bythe Chisquare Test. The observed incidence of side reactions for bothquinidine hydrochloride and quinidine polygalacturonate were notstatistically significant for this study. There were no side reactionsobserved after the administration of dihydroquinidine polygalacturonate.

These unusual properties of the new glycose acid derivatives ofdihydroquinidine are in contrast to the reported research findings withhydroquinidine per se, in that its pharmacologic effect is identical tothat of quinidine alkaloid and also that dihydroquinidine possesses noclinical advantages over the conventional quinidine preparations.Furthermore, this unusual and desirable property of dihydroquinidinepolygalacturonate and dihydroquinidine galacturonate is not due to anyvariations in the potency of the dihydroquinidine moiety, since thislatter compound has been described as being only slightly more potentthan quinidine by some investigators and of equal or lesser potency byothers. Neither can the clinical differences between dihydroquinidineand quinidine be ascribed to a preferential solubility and absorption ofthe former drug, since the solubility and absorption of both thesecompounds have been found to be virtually the same. This finding is ofparticular clinical significance since it affords a means for correctingcardiac arrhythmias which are not amenable to treatment with a quinidinecompound either as quinidine inorganic acid salts or quinidinepolygalacturonate. The advantage to the physician of having available adrug which exhibits a more intensive effect in controlling heart rhythmcannot be minimized. Thus, the superiority of dihydroquinidinepolygalacturo nate over quinidine polygalacturonate opens a new avenueof therapy for the cardiologist in the management of the patient withcardiac arrhythmias. These unusual and desirable antiarrhythmic propertyof these new agents which occurs in those patients who have been foundto be refractory to the conventional salts of quinidine, is a findingwhich cannot 'be predicted on the known behavior of dihydroquinidine.

Dihydroquinidine polygalacturonate and dihydroquinidine galacturonatemay be prepared through the interaction between polygalacturonic acid orgalacturonic acid and dihydroquinidine in an inert medium. Therespective compounds also may be formed through the interaction of thealkali salts of the polygalacturonic acid or galacturonic acid with theacid salt of the dihydroquinidine, as for example, dihydroquinidinesulfate, or dihydroquinidine hydrochloride. When dihydroquinidinepolygalacturonate is being prepared, it is first necessary to determinethe neutralization equivalent of the polygalacturonic acid in order thatits combining power with the dihydroquinidine base be known. Thisneutralization equivalent will vary with the polymer chain length whichmay range in molecular weight of from 20,000 to 80,000. The polymer iscomposed of units of galacturonic acid and consequently the saltdihydroquinidine polygalacturonate consists of multiples ofdihydroquinidine galacturonate which may range from 50 to 400 units ormore. In the course of conducting this reaction, the separate componentsare dispersed, or dissolved, in equal portions of the inert solvent.Examples of the said inert solvents which may be used are water,alkanols of from 1 to 6 carbons, acetone and mixtures of these. Apreferred inert medium is isopropyl alcohol. The alkaline component isadded slowly to the acid component while the mixture is being stirredand gently heated (no greater than 50 C.). When all of the base moietyhas been added, the stirring is continued until the pH of the reactionmixture is between pH 4 and pH 7. The solvent is then evaporated and theresidue extracted with chloroform, dried and washed with water.

Dihydroquinidine polygalacturonate is obtained as a tannish to creamywhite solid, with a characteristic melting point, which analyzes in goodagreement with its theoretical values for carbon, hydrogen and nitrogen.The molecule is somewhat hygroscopic, containing two molecules of waterof hydration. The ultraviolet spectrum obtained for this compoundestablishes the presence of the dihydroquinidine moiety and on treatmentwith aqueous alkali it is decomposed to yield a precipitate of theinsoluble dihydroquinidine base while an aqueous acid solutionprecipitates the polygalacturonic acid moiety from a dispersion of thecompound. Dihydroquinidine polygalacturonate is slightly soluble inwater but insoluble in methanol, ethanol, chloroform and ether.The'bitter taste of dihydroquinidine is modified by reacting it withpolygalacturonic acid. The compound is stable for further pharmaceuticalmanufacturing.

Dihydroquinidine galacturonate is obtained through the interreaction ofstoichiometric proportions of dihydroquinidine base and galacturonicacid in an inert medium, such as water, alkanols of from 1 to 6 carbons,or mixtures of these. The reaction is carried out in a suitable glassvessel to which is first added a solution of the galacturonic acid andwith the aid of gentle heat and with stirring, small increments ofdihydroquinidine base are added to this. When all of thedihydroquinidine base has been added, the solution is warmed to refluxtemperature, allowed to cool to room temperature and set aside tocrystalize in an ice-chest.

Dihydroquinidine galacturonate is a tan to white crystaline solid whichmelts at l34-l36 C. It is soluble in water and alcohol and insoluble inether and chloroform. Although the aqueous solution darkens on exposureto air and light, it is stable for pharmaceutical compounding purposes.It has the characteristic ultraviolet spectrum of dihydroquinidine andon treatment with alkali is decomposed so that the dihydroquinidine baseprecipitates.

When it is desired to utilize these new compounds in therapy, they maybe administered in the form of tablets, capsules, powders, granules, orsuppositories. Liquid dosage forms such as syrups, solutions, elixirsand tinctures may also be utilized. Irrespective of the dosage formselected, the concentration of active compound per unit dose ranges from200 mg. to 800 mg. The new compounds may be administered from 1 to 5times daily in order to achieve a conversion of the arrhythmia a normalsinus rhythm. Maintenance therapy will usually require from 200 to 400mg. of the active compound administered once or twice daily.

In certain circumstances it may be desired to utilize parenteral therapyto achieve the antiarrhythmic effect.

A solution of dihydroquinidine galacturonate may be utilized forparenteral therapy and a dosage of from 200 mg. to 400 mg. isadministered by intramuscular or intravenous injection. Although cautionmust be exercised when intravenous injection is utilized, the compoundpossesses sufiicient freedom from local toxicity to be usedsatisfactorily by the intramuscular route. In practice it will be founddesirable to dissolve the therapeutic dose requirement in a volume offrom 2 to 4 cc., so that each 2 cc. of solution will contain 200 mg. ofdihydroquinidine galacturonate. It should be noted that the same totaldose requirements are necessary to reverse the cardiac arrhythmias whenthese drugs are administered by either the oral or the parenteralroutes, so that the initial dosage requried to reverse the arrhythmias,remains from 200 to 800 mg. of dihydroquinidine galacturonate, with themaintenance dosage of 200 to 400 mg. per day of the parenteral solution.Dihydroquinidine polygalacturonate exhibits an unexpected increasedsolubility in aqueous fluids. While it should be expected that theformation of a polymeric compound would render the resultant productinsoluble in aqueous fluids, a contrary condition was found to be inexcess of percent and specifically, about 8.5 percent.

When it is desired to utilize the subject compounds in therapy tocorrect cardiac arrhythmias then the respective dosage forms describedabove are administered for a series of 5 doses, at 2 to 3 hour intervalsfor 1 day. This course of therapy will convert the arrhythmia to anormal sinus rhythm in the majority of cases. However, in those patientswherein the arrhythmia still persists, a second and even a third courseof therapy may be utilized. After the achievement of a normal sinusrhythm, maintenance dosage of from 200 mg. to 400 mg. administered onceor twice daily, will generally be found satisfactory to maintain thenormal sinus rhythm. Parenterally, the administration ofdihydroquinidine galacturonate will cause a satisfactory maintenanceeifect when administered in a dosage range of 200 mg. to 400 mg. perday. When the pharmaceutical dosage forms of dihydroquinidinepolygalacturonate are compared with those of quinidinepolygalacturonate, unexpected advantages are observed. Dihydroquinidinepolygalacturonate will be found to cause a more pronounced action whichpersists for a longer period than that of quinidine polygalacturonate aswell as quinidine inorganic acid salts. There are no noxious sidereactions such as nausea and diarrhea after the administration of thenew compounds and they are excreted from the body at a rate which doesnot lead to accumulation. This favorable rate of excretion permits theadministration of multiple dosages without additive effects andcumulative toxicity. The rapid onset of action and the uniform bloodlevels resulting after the administration of dihydroquinidinepolygalacturonate permits a more desirable control of the cardiacarrhythmia than has hitherto been posisble with derivatives of thecinchona plant. The active compounds are readily assimilated andabsorption and the beneficial cardiotonic effects will be observed totake effect within 15 minutes after administration.

The following examples illustrate the scope of this invention.

EXAMPLE 1 The neutralization equivalent of a sample of polygalacturonicacid is determined by titration with onetenth normal alkali.

In a round-bottom, three-neck flask fitted with a stirrer, a droppingfunnel and a condenser, is placed 1 liter of 50 percent (vol/vol.)mixture of isopropyl alcohol and water. To this is added, with stirring,100 gm. of polygalacturonic acid and when complete dispersion has beenobtained, the stoichiometric equivalent of dihydroquinidine alkaloiddissolved in just sufficient isopropyl alcohol, is slowly added. The pHof the reaction mixture is determined periodically and the mixture isgently warmed (below 50 C.). After about 4 hours or when the pH hasstabilized between the range of from pH 4 to pH 7, the stirring isstopped and the mixture cooled to 0 C., and filtered. The solvent isthen evaporated under reduced pressure mm./Hg) and the residue extractedwith two volumes of hot chloroform and dried. The dried powder is thensuspended in two volumes of 50 percent water-methanol and filtered. Theinsoluble powder is dried and is dihydroquinidine polygalacturonate. Thecompound is tannish to white in color and melts (with decomposition) at205207 C. and possesses two molecules of water of hydration. Theempirical formula for the compound is C H N O H O, with a calculatedmolecular weight of 556.54. The compound is insoluble in chloroform,ether and methanol, and slightly soluble in water. It possesses acharacteristic ultraviolet spectrum for dihydroquinidine and acharacteristic infrared spectrum which is different from that of itscomponents or a mixture of these. It analyzes in good agreement with itstheoretical values of carbon, nitrogen and hydrogen.

Analysis.Theory: carbon, 56.1%; hydrogen, 7.2%; nitrogen, 5.0%. Found:carbon, 55.87%; hydrogen, 7.09% nitrogen, 4.66%.

EXAMPLE 2 In place of the isopropyl alcohol described in Example 1, maybe substituted, wholly or in part, a member of the class of alkanolshaving 1 through 4 carbon atoms, water and mixtures of these, theremainded of the steps being the same and the compound obtained isdihydroquinidine polygalacturonate, cor-responding in every way to thatdescribed in Example 1 above.

EXAMPLE 3 A solution containing 200 grams of polygalacturonic acid intwo liters of 60 percent mixture of methanol-water is prepared, with theaid of an exact neutralization equivalent of sodium hydroxide. Thesolution is stirred and to this is added a solution consisting of anexact equivalent of dihydroquinidine sulfate (based upon theneutralization equivalent determined for the polygalacturonic acid). Thedihydroquinidine sulfate is dissolved in a just sufficient quantity of60 percent mixture (vol./vol.) methanol-water. The mixture is warmed to60 C. and after the pH of the solution has stabilized within the rangeof pH 4 to pH 6, an additional liter of methanol is added. The mixtureis then cooled to 0 C. and filtered. The solvent is evaporated todryness, the residue is washed with two 50 cc. portions of water anddried. The resulting product is dihydroquinidine polygalacturonate whichmelts at 205207 C. and corresponds in every way to that obtained as aresult of Example 1.

EXAMPLE 4 In place of dihydroquinidine sulfate used in Example 3 above,may be substituted in equimolar proportions dihydroquinidine chloride,dihydroquinidine bromide and dihydroquinidine nitrate.

In place of the sodium hydroxide used to neutralize the polygalacturonicacid in Example 3 above, may be substituted, in equimolar proportions, ametal hydroxide, carbonate and bicarbonate in which the molecular weightof the metal ion is less than 55, as for example, lithium, potassium,calcium, magnesium and aluminum.

EXAMPLE 5 To a solution of one-tenth mol of galacturonic acid dissolvedin 500 cc. of butyl alcohol is added exactly onetenth mol ofdihydroquinidine. The mixture is stirred and warmed to refluxtemperature for 2 hours and the solvent evaporated to dryness underreduced pressure. The residue is extracted with chloroform and dried.The resulting product is dihydroquinidine galacturonate which melts at134 to 136 C. and is a tan to white crystalline substance, soluble inwater and methanol, ethanol, acetone and insoluble in chloroform andether. The ultraviolet spectrum is characteristic for dihydroquinidineand the compound is decomposed by alkali to result in an insolubleprecipitate of dihydroquinidine base.

EXAMPLE 6 In place of the butyl alcohol used in Example 5 above, may besubstituted a member of the group of alkanols containing from 1 through4 carbon atoms, Water and mixtures of these. The remainder of the stepsare the same and the resultant product is identical to that obtained asa result of Example 5.

EXAMPLE 7 To a solution of 1 mol of sodium galacturonate dissolved in 1liter of ethanol is added one mol of dihydroquinidine chloride dissolvedin 1 liter of ethanol, and 500 mg. of copper powder. The mixture isstirred and heated to about 60 C. A copious precipitate forms as thereaction progresses, and after 4 hours the stirring is stopped; themixture filtered and the solvent evaporated to dryness. The residue isextracted with 25 cc. of chloroform, dried and dissolved in a justsufficient quantity of hot isopropyl alcohol. The solution is filtered,set aside to crystallize in an ice-chest. The crystals are collected ona filter, dried and melt at 134136 C. and correspond to dihydroquinidinegalacturonate.

EXAMPLE 8 In place of the sodium galacturonate used in Example 7 above,may be substituted in equimolar amounts a metal hydroxide, carbonate andbicarbonate in which the molecular weight of the metal ion is less than55, as for example, lithium, potassium, calcium, magnesium and aluminum.

In place of the dihydroquinidine chloride used in Example 7 above, theremay be substituted in equimolar quantities, dihydroquinidine sulfate,dihydroquinidine nitrate and dihydroquinidine bromide.

EXAMPLE 9 When it is desired to administer the new compounds in therapy,then they may be utilized in the form of tablets, capsules, powders,granules or suppositories. The quantity of active ingredient in therespective pharmaceutical dosage form ranges 200 mg. to 800 mg. per unitdose. For the preparation of the tablets, capsules, powders andgranules, a basic granulation mixture is prepared by mixing the activecompound with from 1 to 10 parts of a pharmaceutically acceptablediluent selected from the group consisting of lactose, sucrose,dextrose, starch, sorbitol, mannitol or mixtures of these. Afterthorough mixing, the whole is wetted with a 50 percent ethanol-watermixture and air-dried. In the preparation of tablets, suitable binders,such as gum acacia and gum tragacanth, are added at a concentration of0.1 percent to 1 percent by weight, and a tablet lubricant, as forexample, magnesium stearate, is added at a concentration of up to 0.5percent by Weight and the whole granulated with ethanol-watergranulating solution, as described above. The granulation is thencompressed into tablets of suitable size and shape, so as to containfrom 200 mg. to 800 mg. of active ingredient per tablet.

In the preparation of capsules, the basic granulation or the activeingredient alone may be filled into a capsule of suitable size andshape. The dosage of active compound per capsule is from 200 mg. to 800mg. of active compound.

In the preparation of powders and granules, the basic granulationdescribed above is utilized. For the preparation of powders, theparticle size of the granulation is reduced to a No. 60 standard meshsize or finer. For the preparation of granules the particle size is thatobtained by passing the granulation mixture through a No. 8 standardmesh screen. Suitable flavoring and coloring matter may be added to thegranules and powders, if desired. For both powders and granules the unitdose is 1 teaspoonful '(5 grams) each unit dose containing from 200 mg.to 800 mg. of active compound.

For the preparation of suppositories the active compound may be mixedwith a pharmaceutically suitable suppository base, as for example, cocoabutter, polyoxyethylene glycol, having an average molecular weight offrom 1500 to 6000 and which are known in the trade as Carbowaxes,spermaceti, glycerol-gelatin suppository base, or any otherpharmaceutically suitable suppository vehicle. The active ingredient isdispersed in the suppository base by means of levigation. Either thecold extrusion process or the hot pour technique may be utilized for themanufacture of suppositories. Each suppository will contain from 200 mg.to 800 mg. of the active compound.

Should it be desired to utilize liquid dosage forms, then these. may beprepared utilizing a pharmaceutically acceptable vehicle such asethanol, glycerin, propylene glycol, sorbitol, water and mixtures ofthese. Suitable flavoring and sweetening agents may be added and syrupmay also be used as a vehicle for the preparation of liquid dosageforms. The active ingredient is dispersed in the preferred liquidpharmaceutically acceptable vehicle, so that each 5 cc. (1 teaspoon)will contain from 200 mg. to 800 mg. of the active compound.

EXAMPLE 10 In place of the dihydroquinidine polygalacturonate used inExample 9, may be substituted in equivalent amounts, dihydroquinidinegalacturonate to prepare tablets, capsules, powders, granules andsuppositories, as well as the liquid dosage forms.

When an aqueous injectable solution of dihydroquinidine galacturonate isdesired, the solution is prepared so that the concentration ofdihydroquinidine galacturonate is from 200 to 400 mg. per cc. ofsolution. Using an aseptic technique, the correct amount ofdihydroquinidine galacturonate is dissolved in the total volume requiredof water-for-injection. Gentle heat may be utilized to achieve solution,but this is not necessary. When all of the dihydroquinidine hasdissolved, the solution is filtered through a selas bacteriologic filterand additional water-for-injection added, so that the final volumecontains from 200 to 400 mg. of dihydroquinidine galacturonate per 2 cc.of solution. The solution is then packaged in amber glass ampules andmay be sterilized by autoclaving.

EXAMPLE 11 When it is desired to correct the cardiac arrhythmias, as forexample, atrial fibrillation, atrial flutter, paroxysmal atrialfibrillation, paroxysmal atrial tachycardia, premature atrialcontractions and premature ventricular con tractions, eitherdihydroquinidine polygalacturonate or dihydroquinidine galacturonate maybe administered in the form of capsules, tablets powders, granules,suppositories and liquid dosage forms. Dihydroquinidine galacturonatemay be injected intramuscularly or intravenously. Irrespective of theroute of administration or the particular dosage form employed, theamounts of the therapeutic compound used will be the same for therespective dosage form selected. Thus, it will be found that 200 mg. to400 mg. of either dihydroquinidine polygalacturonate or dihydroquinidinegalacturonate administered every 2 to 3 hours for 5 doses, will revertthe arrhythmia to a normal sinus rhythm in a preponderance of patients.A maintenance dosage of 200 to 400 mg., once or twice a day, of therespecitve active compound may then be instituted to sustain thetherapeutic effects observed.

When there is no urgency in obtaining a reversion of the arrhythmia, thepatient may be prescribed a dosage of from 200 to 400 mg. of theselected compound, three to four times daily, for a period of 3 to 4days. If the desired response is not obtained with this dosage level,the total daily requirement is increased by 200 mg. of the selectedcompound, per day, for an additional two day period, with subsequentincreases of 200 mg. of the compound per day after similar intervals,until a normal sinus rhythm is achieved.

A maintenance regimen of from 200 to 400 mg. once or twice a day, of theselected compound, as for example, dihydroquinidine polygalacturonate,dihydroquinidine galacturonate, is then instituted to sustain thetherapeutic results achieved. The utilization of this slower procedurefor reversing the cardiac arrhythmia will be found to be successful in apreponderant number of patients who are refractory to other forms ofantiarrhythmic therapy.

I claim:

1. A compound selected from the group consisting of dihydroquinidinegalacturonate and dihydroquinidine polygalacturonate.

2. A compound of claim 1, said compound being dihydroquinidinegalacturonate.

13 3. A compound of claim 1, said compound being di- 8/1936 Haegland260284 3/1938 Salzberg 260284 14 2,230,631 2/1941 Thomas 2602842,878,252 3/1959 Halpern 260284 3,316,242 4/ 1967 Sasm'on 260209.5

DONALD G. DAUS, Primary Examiner US. Cl. X.R. 260209.5; 424259

